Novel Hybrids of Pyrazolidinedione and Benzothiazole as TZD Analogues. Rationale Design, Synthesis and In Vivo Anti-Diabetic Evaluation

Abstract

Background: The development of new classes of blood glucose–lowering medications has increased the number of treatment opportunities available for type 2 diabetes. Nevertheless, long term complicated treatments and side effects of available antidiabetic therapies have urged huge demands for effective affordable anti-diabetic agents that can lessen negative health consequences. In this sense, the exploration of alternative medicinal remedies associated with new significant antidiabetic efficiencies with minimized adverse effects is an active domain of research. Objective: The aim of this study was to synthesize a series of benzothiazole-pyrazolidinedione hybrids and evaluate their antidiabetic activity along with molecular docking and in silico analysis. Methods: The hybrids were synthesized by a multi-step synthesis and were further subjected for in vivo anti-hyperglycemic assessment on rat models of type II diabetes. Molecular modelling study was undertaken against peroxisome proliferator-activated receptor γ (PPARγ) to highlight possible key interactions. Results: Docking studies revealed that appropriate substituents on benzothiazole ring interacted favorably with the hydrophobic Ω-pocket of PPARγ binding site resulting in improving their antihyperglycemic activity. All the synthesized hybrids manifested promising anti-hyperglycemic potency. Excitingly, 5a, 5b and 5c were even more potent than the standard drug. Conclusion: The newly synthesized hybrids can be considered as a new class of antidiabetic agents and this study provided useful information on further optimization.